ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3851G>A (p.Arg1284Gln) (rs149462407)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081471 SCV000289344 likely benign Colorectal cancer, susceptibility to, 12 2020-12-08 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000455463 SCV000540092 uncertain significance not specified 2016-10-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has not been reported in affected individuals. It is present in ExAC at a MaxMAF of 0.1%. It is classified in ClinVar as Likely Benign (1 star - Invitae). 11 mammals have a Gln at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000455463 SCV000602036 benign not specified 2019-12-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566885 SCV000671267 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-17 criteria provided, single submitter clinical testing Thep.R1284Qvariant (also known as c.3851G>A), located in codingexon31 of thePOLEgene, results from a G to A substitution at nucleotide position 3851. Thearginineatcodon1284 is replaced by glutamine, an amino acid with highly similar properties. This variant was previously reported in theSNPDatabaseasrs149462407. Based on data from theNHLBIExomeSequencing Project (ESP), the A allele has an overall frequency of approximately 0.08% (10/12856) total alleles studied, having been observed in 0.02% (1/4356) African American alleles and 0.11% (9/8500) European American alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of p.R1284Qremains unclear.
GeneDx RCV000455463 SCV000729737 likely benign not specified 2017-09-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
PreventionGenetics,PreventionGenetics RCV000679625 SCV000806767 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000455463 SCV000920079 likely benign not specified 2018-12-14 criteria provided, single submitter clinical testing Variant summary: POLE c.3851G>A (p.Arg1284Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 267992 control chromosomes. The observed variant frequency is approximately 43 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3851G>A in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (3 likely benign and 3 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000679625 SCV001148891 uncertain significance not provided 2019-03-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355018 SCV001549774 likely benign Carcinoma of colon no assertion criteria provided clinical testing The POLE p.Arg1284Gln variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs149462407) as "With other allele", and in ClinVar (classified as likely benign by Invitae, GeneDx, Quest Diagnostics Nichols Institute San Juan Capistrano and as uncertain significance by Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was identified in control databases in 167 of 267992 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 136 of 120242 chromosomes (freq: 0.001), African in 5 of 22974 chromosomes (freq: 0.0002), Other in 6 of 6324 chromosomes (freq: 0.001), Latino in 12 of 34274 chromosomes (freq: 0.0003), East Asian in 1 of 18716 chromosomes (freq: 0.0001), Finnish in 5 of 24868 chromosomes (freq: 0.0002), and South Asian in 2 of 30682 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish population. The p.Arg1284 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000679625 SCV001741157 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000679625 SCV001808871 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics,Academic Medical Center RCV000679625 SCV001917867 likely benign not provided no assertion criteria provided clinical testing

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